Mammalian reoviruses infect cells in the central nervous system (CNS) of newborn mice, leading to apoptosis and lethal encephalitis. Reovirus-induced apoptosis requires engagement of cell-surface receptors, intracellular signaling, and activation of transcription factor NF-kappaB. Experiments are proposed to identify viral and cellular determinants of reovirus-induced apoptosis and elucidate the significance of this host-cell response in vivo. The central hypothesis of the proposed research is that NF-kappaB activation and apoptosis are required for reovirus-induced CNS disease. In Specific Aim 1, steps in reovirus replication that lead to NF-kappaB activation and apoptosis will be defined. In Specific Aim 2, intracellular signaling events required for reovirus-induced NF-kappaB activation and apoptosis will be identified. In Specific Aim 3, the role of NF-kappaB activation and apoptosis in reovirus virulence will be investigated. These experiments will provide an enhanced understanding of how viruses perturb host-cell-signaling pathways to cause cell death and disease. Information gained from these studies should foster development of new antiviral strategies designed to inhibit apoptosis.